1. Field of the Invention
This invention relates to compounds having benzothiophene groups, in particular those binding to nucleic acids and having anti-bacterial properties, and methods for their use.
2. Description of Related Art
A number of naturally occurring or synthetic compounds bind to double stranded nucleic acid, especially double stranded DNA (xe2x80x9cdsDNAxe2x80x9d). Some bind to the major groove, while others bind to the minor groove. Still others intercalate between adjacent base pairs. Combination binding modes are known, in which a compound has binding interactions with more than one nucleic acid site.
The natural products distamycin and netropsin represent a class of DNA-binding compounds that has been studied over the years: 
Structurally, distamycin and netropsin are heteroaromatic polyamides, having as their core structural motif N-methylpyrrole carboxamide residues. They bind to the minor groove, their crescent molecular shapes providing a conformational fit within the groove. The binding occurs with a preference for A,T rich dsDNA tracts.
A number of heteroaromatic polyamides have been synthesized elaborating on the distamycin/netropsin motif, with the objective of enhancing or varying biological properties, increasing binding affinity to dsDNA, and/or improving specificity in base pair sequence recognition. The use of synthetic heteroaromatic polyamides in therapeutics has been proposed, for example, in Dervan et al., U.S. Pat. No. 5,998,140 (1999); Dervan et al., WO 00/15209 (2000); Dervan, WO 00/15773 (2000); and Gottesfeld et al., WO 98/35702 (1998).
The effect of structural variations in the heteroaromatic ring has been a focus of extensive research. See, e.g., reviews by Bailly et al., Bioconjugate Chemistry, Vol. 9, No. 5, pp. 513-538 (1998) and Neidle, Nat. Prod. Rep. 2001, 18, 291-309. Alternative heteroaromatic rings reported in the art include furan, imidazole (especially N-methylimidazole), isoxazole, oxazole, pyrazole, pyridine, thiophene, triazole rings, and others. Art that may be relevant to the use of benzothiophene groups in DNA binding compounds includes Boger et al., J. Am. Chem. Soc., 2000, 122, 6382; Kutyavin et al., U.S. Pat. No. 5,801,155 (1998); Tidwell et al., U.S. Pat. No. 6,172,104 (2001); Cozzi et al., WO 98/21202 (1998); Cozzi et al., WO 99/50266 (1999); and Turin et al., WO 01/19792 (2001).
The present invention provides benzothiophene compounds of the formula 
including the pharmaceutically acceptable salts thereof.
Each R5 is independently H, F, Cl, Br, I, CN, OH, NH2, a substituted or unsubstituted (C1-C12)alkyl group, a substituted or unsubstituted (C1-C12)alkoxy group, or a substituted or unsubstituted (C1-C12)heteroalkyl group. Each R2 is independently H, a substituted or unsubstituted (C1-C12)alkyl group, or a substituted or unsubstituted (C1-C12)heteroalkyl group. Subscript m is an integer from 1 to 25, inclusive. Z is either O or N, with n being 1 if Z is O and 2 if Z is N. Each Y is independently a branched or unbranched, substituted or unsubstituted (C1-C5)alkylene group or a substituted or unsubstituted, aromatic or heteroaromatic ring system, wherein the ring system can comprise a 5- or 6-member aromatic or heteroaromatic ring or fused 6,6 or 6,5 aromatic or heteroaromatic rings, with the proviso that at least one Y is a substituted or unsubstituted aromatic or heteroaromatic ring system. Preferably, at least one Y is a 5- or 6-member heteroaromatic ring. More preferably, Y in the moiety xe2x80x94(NHxe2x80x94Yxe2x80x94CO)xe2x80x94 immediately adjacent to the moiety 
is a 5- or 6-member heteroaromatic ring.
Preferably, each moiety xe2x80x94(NHxe2x80x94Yxe2x80x94CO)xe2x80x94 is independently selected from the group consisting of
(a) moieties M1 of the formula 
xe2x80x83wherein one of X1, X2, and X3 is a ring vertex selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, and xe2x80x94NR2xe2x80x94, and the other two of X1, X2, and X3 are ring vertices selected from the group consisting of xe2x95x90Nxe2x80x94 and xe2x95x90CR1xe2x80x94;
(b) moieties M2 of the formula 
xe2x80x83wherein x is 0 or 1 and each R15 is independently H, OH, NH2, or F;
(c) moieties M3 of the formula 
xe2x80x83wherein each L is independently a divalent moiety separating xe2x80x94NHxe2x80x94 and xe2x80x94(Cxe2x95x90O)xe2x80x94 by 3 or 4 atoms; and
(d) moieties M4 of the formula 
xe2x80x83with the proviso that at least one moiety xe2x80x94(NHxe2x80x94Yxe2x80x94CO)xe2x80x94 is M1 or M4;
and the compound contains a basic group having a pKb of 12 or less or a quaternized nitrogen group.
Preferably, at least one moiety xe2x80x94(NHxe2x80x94Yxe2x80x94CO)xe2x80x94 is a moiety M1. More preferably, the moiety xe2x80x94(NHxe2x80x94Yxe2x80x94CO)xe2x80x94 immediately adjacent to the residue 
is a moiety M1.
In the preceding formulae R1 and R2 are as previously defined.
Preferably, R1 is hydrogen, halogen (F, Cl, Br, or I, especially F or Cl), a (C1-C5)alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, pentyl, and the like, a (C1-C5)alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like, hydroxy, or cyano. Preferably, each R2 is H or a (C1-C5)alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, pentyl, and the like.